8Beta-substituted-11-beta-pentyl-and 11-beta-hexyl-estra-1,3,5(10)-triene derivatives

ABSTRACT

This invention describes the new 8β-substituted estratrienes of general formula (I),  
     in which R 2 , R 3 , R 6 , R 6′ , R 7 , R 7′ , R 14 , R 15 , R 15′ , R 16 , R 16′ , R 17 , and R 17′  have the meanings that are indicated in the description, R 8  means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical, and R 11  means an n-pentyl or n-hexyl radical, as pharmaceutical active ingredients that have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably exert a preferential contraceptive action on the ovary without stimulating the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The invention also describes the use of these compounds for contraception in men as well as the treatment of benign or malignant proliferative diseases of the ovary, such as, e.g., ovarian cancer, or granulosa cell tumors.

FIELD OF THE INVENTION

[0001] This invention relates to new compounds as pharmaceutical active ingredients that have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo exert a contraceptive action by their preferential action on the ovary, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.

[0002] The chemical compounds are novel, steroidal, tissue-selective estrogens.

BACKGROUND OF THE INVENTION

[0003] Contraceptive methods with chemical compounds are common with women who do not want to become pregnant. The following chemical methods of female contraception are now available to us:

[0004] (A) The endocrine principle: suppression of ovulation by inhibition of the release of gonadotrophin and thus the ovulation

[0005] (B) Prevention of the ascension of sperm through the female reproductive tract to the fallopian tube where the fertilization takes place

[0006] (C) Prevention of the implantation or nidation of a fertilized embryo in the uterus

[0007] (D) Spermicide

[0008] (E) Abortion-inducing agent

[0009] Oral contraceptives that consist of the most varied combinations of an estrogen with a gestagen are the most frequently used contraceptive of women. They act according to the endocrine principle. Although such contraceptives are very effective, undesirable side effects may occur, however, such as, e.g., irregular bleeding, nausea, vomiting, depression, weight gain or headaches. More serious diseases are also sometimes observed, such as thrombo-embolisms, stroke, liver adenoma, gallbladder diseases or hypertension, which indicate that no effective contraceptives without side effects are now available. The medical necessity for a new contraceptive method thus exists.

[0010] An ideal contraceptive method is a method that operates directly on the ovarian follicle without influencing the endocrine hypothalamo-pituitary-ovarian axis. This can be achieved with a chemical compound that impairs the folliculogenesis, for example by destroying a paracrine interaction between the egg cell and the granulosa cells, and thus provides that

[0011] (a) the follicle program cannot proceed adequately, so that an incompetent egg cell matures, which is ovulated but cannot be fertilized, or

[0012] (b) the follicle program cannot proceed adequately, so that an incompetent egg cell matures, which is ovulated and fertilized but does not result in any pre-implantation development, or

[0013] (c) the folliculogenesis is possible only to a limited extent, and it does not result in any ovulation.

[0014] Follicular growth is the development of an ovarian follicle from the primordial stage to the large antral follicle that is ready to burst. Only an optimally built-up antral follicle has the potential to ovulate a mature egg cell. Patients with ovarian infertility, e.g., PCOS (=polycystic ovarian syndrome) patients, have a disrupted folliculogenesis associated with hormonal and ovulation disorders as well as insufficiently matured egg cells (Franks et al. (2000) Mol Cell Endocrinol 163: 49-52).

[0015] There are always more indications that the early stages of folliculogenesis, i.e., the development steps from the primordial follicle to the early antral follicle, are gonadotrophin-independent, but it is still not conclusively explained which of the identified autocrine or paracrine factors (Elvin et al. (1999), Mol Cell Endocrinol 13: 1035-1048; McNatty et al. (1999), J Reprod Fertil Suppl 54: 3-16) are the most important in early folliculogenesis. Gonadotrophins, such as, e.g., FSH (follicle-stimulating hormone), however, are mainly involved in the late steps of folliculogenesis, i.e., the development from the early antral follicle to the large ovulatory follicle. Additional modulators of folliculogenesis are also discussed in the late folliculogenesis, however (Elvin et al. (1999), Mol Cell Endocrinol 13: 1035-1048).

[0016] Estrogen receptor β (ERβ) was recently discovered as a second subtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365). The expression pattern of ERβ differs from that of the ERα (Kuiper et al. (1996), Endocrinology 13.8: 863-870). Whereas an expression of ERα could be detected in almost all organs studied, the highest expression of ERβ in female animals was found in the ovary and in male animals was found in the prostate (Couse et al. (1997) Endocrinology 138: 4613-4621). In the ovary, a clear ERβ expression in follicles is shown in almost all stages of development: While in the follicles ERα is expressed only in the outside follicle cells (thecal cells), a strong expression of ERβ is present in the estradiol-producing granulosa cells. Based on the varying cell distribution of ERα and ERβ in the ovarian follicle, it is thus to be expected that the interaction of a ligand with ERα or ERβ will lead to different cellular responses. The fact that ERα and ERβ are functionally different was recently confirmed by the successful production of ERα and ERβ knockout mice (Couse et al. (1999), Endocrine Reviews 20: 358-417). ERα is consequently decisively involved in the function of the uterus, the mammary gland, the control of the sexual-endocrine axis, whereas ERβ is included predominantly in the processes of ovarian physiology, especially folliculogenesis and ovulation.

[0017] Another organ system with high ERβ expression is the testis (Mosselmann et al. 1996 Febs Lett 392 49-53) including the spermatides (Shugrue et al. 1998, Steroids 63: 498-504). The fact that ERβ is functional in the male animal also arises through studies of ERα-(ERKO) or ERβ-(βERKO)-knockout mice: Male ERKO mice (Hess, R. A. et al. 1997, Nature 390: 509-512) have considerable fertility disorders. As a result, the important function of estrogens with respect to maintaining testis function relative to fertility is confirmed.

[0018] ERα and ERβ have significantly different amino acid sequences in their ligand binding domains and transactivation domains. This suggests that (1) ER subtypes bind to their ligands with different affinity and (2) ligands can show a different agonistic and/or antagonistic potential on the two receptor subtypes.

[0019] Patent Applications WO 00/47603, WO 00/63228, PCT/EP00/10804, DE 100 19167.3, U.S. No. 60/207,370 as well as publications (Sun et al. (1999), Endocrinology 140: 800-804; Stauffer et al. (2000), J Comb Chem 2: 318-329) recently showed that steroidal and nonsteroidal ligands with high affinity to ERα and ERβ were found. Some compounds were considerably stronger agonists/antagonists at ERα, whereas other compounds were stronger agonists/antagonists at ERβ.

[0020] In WO 00/31112, new steroidal compounds based on the building block of the estradiol that is unsubstituted in 8-position are described that carry in 11β-position a hydrocarbon radical that contains an individual linear chain with a length of 5 to 9 carbon atoms. These compounds have an ERα-agonistic/ERβ-antagonistic profile of action. Based on this mixed estrogen receptor profile, these compounds are suitable as improved estrogens for the treatment of estrogen-induced disorders and for contraception together with a gestagen.

[0021] In U.S. No. 60/271,409 (un-prepublished), in vivo findings are shown for the first time, from which it is clear that Erβ-selective agonists result in an improvement of the folliculogenesis, whereas Erβ-selective antagonists reduce the fertility, i.e., the ovulation rate.

[0022] The object of this invention is therefore to provide compounds that have in vitro a dissociation with respect to the binding to estrogen receptor preparations from rat prostates and rat uteri and that exert a contraceptive action in vivo by their preferential action on the ovary without influencing other estrogen-sensitive organs, such as, e.g., the uterus or the liver. These compounds also are to be used for contraception in men as well as for treating benign or malignant proliferative diseases of the ovary.

[0023] This object is achieved by the provision of the compounds of general formula I

[0024] in which

[0025] R²: means hydrogen, halogen (F, Cl, Br, I);

[0026] a radical R¹⁸ or R¹⁸O, whereby R¹⁸ means hydrogen, an alkyl or acyl radical (both straight-chain or branched-chain, saturated or unsaturated with up to 6 carbon atoms), a trifluoromethyl group;

[0027] a radical R¹⁹SO₂O, whereby R¹⁹ means an R²⁰R²¹N group, in which R²⁰ and R²¹, independently of one another, mean hydrogen, a C₁-C₅-alkyl radical, a group C(O)R²², in which R²² means a hydrocarbon radical (optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, partially or completely halogenated) with up to 10 carbon atoms, an optionally substituted C₃-C₇-cycloalkyl radical, an optionally substituted C₄-C₁₅-cycloalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or, together with the N-atom, means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical);

[0028] R³: means R¹⁸O, R¹⁹SO₂O or OC(O)R²², with R¹⁸, R¹⁹ and R²² in the meaning that is indicated under R², and in addition R¹⁸ means an aryl, hetaryl or aralkyl radical;

[0029] R⁶, R^(6′): each mean hydrogen or R⁶ means an additional bond with R⁷;

[0030] R⁷, R^(7′): each mean hydrogen, or R⁷ means an additional bond with R⁶;

[0031] R⁸: means an alkyl or alkenyl radical (straight-chain or branched-chain, partially or completely halogenated), in each case with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;

[0032] R¹¹: means an n-pentyl or n-hexyl radical;

[0033] R¹⁴: means hydrogen or an additional bond with R¹⁵;

[0034] R¹⁵: means hydrogen or an additional bond with R¹⁴ or R¹⁶;

[0035] R¹⁶: means hydrogen or an additional bond with R15;

[0036] R^(15′), R^(16′): independently of one another, mean hydrogen, halogen, a group R¹⁸O, R¹⁹SO₂O or OC(O)R²², with R¹⁸, R¹⁹ and R²² in the meaning that is indicated under R²;

[0037] R¹⁷, R^(17′): each mean a hydrogen atom;

[0038] a hydrogen atom and a halogen atom;

[0039] a hydrogen atom and a benzyloxy group;

[0040] a hydrogen atom and a group R¹⁹SO₂—O—;

[0041] a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²;

[0042] a group R¹⁸—O— and a group R¹⁸—;

[0043] a group R¹⁸—O— and a group —O—C(O)R²², with R¹⁸, R¹⁹ and R²² in the meaning that is indicated under R²; or

[0044] R¹⁷, R^(17′): together mean a group ═CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogen atom, or together represent an oxygen atom.

[0045] The possible substituents at carbon atoms 6, 7, 15, 16 and 17 can be respectively in α- or β-position.

[0046] In the compounds of general formula I as well as in the claimed partial structures, a fluorine, chlorine, bromine or iodine atom can always stand for a halogen atom; a fluorine atom is preferred in each case.

[0047] In particular, the hydrocarbon radicals, which can be partially or completely halogenated, are fluorinated radicals.

[0048] Hydrocarbon radical R¹⁸ is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl or hexyl radical.

[0049] Alkoxy group OR¹⁸ can contain 1 to 6 carbon atoms, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.

[0050] Representatives of the C₁-C₅-alkyl radicals R²⁰ and R²¹ are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl.

[0051] As representatives of straight-chain or branched-chain hydrocarbon radicals R²² with 1 to a maximum of 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl can be mentioned; methyl, ethyl, propyl and isopropyl are preferred.

[0052] As perfluorinated alkyl groups, for example, trifluoromethyl, pentafluorethyl and nonafluorobutyl can be mentioned. Representatives of the partially fluorinated alkyl groups are, for example, 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 6,6,6,5,5,4,4,3,3-nonafluorohexyl, etc.

[0053] As a C₃-C₇-cycloalkyl group, a cyclopropyl, butyl, pentyl, hexyl or heptyl group can be mentioned.

[0054] A C₄-C₁₅-cycloalkylalkyl radical has 3 to 7 carbon atoms in the cycloalkyl portion; typical representatives are the cycloalkyl groups that are mentioned directly above. The alkyl portion has up to 8 carbon atoms.

[0055] As examples of a C₄-C₁₅-cycloalkylalkyl radical, the cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, and cyclopentylpropyl group, etc., can be mentioned.

[0056] In terms of this invention, an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.

[0057] Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2-or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.

[0058] As substituents for an aryl or heteroaryl radical, for example, a methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C₁₋₈-alkyl) or di(C₁₋₈-alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, can be mentioned.

[0059] An aralkyl radical is a radical that contains in the ring up to 14, preferably 6 to 10, C atoms and in the alkyl chain 1 to 8, preferably 1 to 4, C atoms. Thus, as aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO₂H, CO₂-alkyl, —NO₂, —N₃, —CN, C₁-C₂₀-alkyl, C₁-C₂₀-acyl, or C₁-C₂₀-acyloxy groups.

[0060] The alkyl groups or hydrocarbon radicals can be partially or completely fluorinated or substituted by 1-5 halogen atoms, hydroxy groups or C₁-C₄-alkoxy groups.

[0061] A vinyl or allyl radical is primarily defined with a C₂-C₅-alkenyl radical.

[0062] One or more hydroxyl groups at C atoms 3, 16 and 17 can be esterified with an aliphatic, straight-chain or branched-chain, saturated or unsaturated C₁-C₁₄-mono- or polycarboxylic acid or an aromatic carboxylic acid or with an α- or β-amino acid.

[0063] Suitable as such carboxylic acids for esterification are, for example:

[0064] Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, elaidic acid.

[0065] Esterification with acetic acid, valeric acid or pivalic acid is preferred.

[0066] Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, and mesaconic acid.

[0067] Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, and isonicotinic acid.

[0068] Esterification with benzoic acid is preferred.

[0069] As amino acids, the representatives of these classes of substances that are known sufficiently to one skilled in the art are suitable, for example, alanine, β-alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.

[0070] Esterification with β-alanine is preferred.

[0071] According to a variant of the invention, compounds of general formula I are preferred, in which

[0072] R² means a hydrogen or halogen atom or a hydroxy group;

[0073] R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²,

[0074] R⁶ and R⁷ each mean a hydrogen atom;

[0075] R^(6′) means a hydrogen atom, a hydroxy group, a group R²² in the meaning that is indicated under R²;

[0076] R^(7′) means a hydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²;

[0077] R⁸ means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl- or prop-1-inyl radical;

[0078] R⁹ means a hydrogen atom or together with R¹¹ an additional bond;

[0079] R¹¹ means an n-pentyl or n-hexyl group;

[0080] R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom;

[0081] R^(16′) means a hydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹, and R²² in each case in the meaning that is indicated under R²;

[0082] R¹⁷ and R^(17′) mean a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², in all above cases with R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²; and

[0083] R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogen atom, or together mean an oxygen atom.

[0084] Another preferred variant of this invention calls for the use of those compounds of general formula I′,

[0085] in which

[0086] R² means a hydrogen atom or a fluorine atom or a hydroxy group,

[0087] R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹, and R²² in each case in the meaning that is indicated under R²;

[0088] R⁶ and R⁷ in each case mean a hydrogen atom;

[0089] R^(6′) means a hydrogen atom or a hydroxy group,

[0090] R^(7′) means a hydrogen atom, a fluorine or chlorine atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²;

[0091] R⁸ means a straight-chain or branched-chain, optionally partially or completely fluorinated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl radical or prop-1-inyl radical;

[0092] R¹¹ means an n-pentyl group or n-hexyl group;

[0093] R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom;

[0094] R^(16′) means a hydrogen atom, a fluorine or chlorine atom or a group R¹⁸—O or —R²², with R¹⁸ and R²² in each case in the meaning that is indicated under R²;

[0095] R¹⁷ and R^(17′) mean a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², in all above cases with R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²; or

[0096] R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogen atom, or together mean an oxygen atom.

[0097] According to another variant, this invention relates to 8β-substituted estra-1,3,5(10)-triene derivatives of general formula I, in which

[0098] Another variant of the invention are estratriene derivatives of general formula I

[0099] in which

[0100] R¹⁷ and R^(17′) mean a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸— and a group —O—C(O)R²², with R¹⁸ and R²² in each case in the meaning that is indicated under R².

[0101] Of these last-mentioned groups, those are preferred in which

[0102] R¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, a C₁-C₄-alkyl group or a C₂-C₄alkenyl group

[0103] and especially preferred are those

[0104] in which

[0105] R¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, a methyl, ethinyl or prop-1-inyl group.

[0106] Preferred according to the invention are the compounds

[0107] 8β-Methyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol

[0108] 8β-ethyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol

[0109] 11β-pentyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0110] 11β-hexyl-8β-methyl-1,3,5(10)-triene-3,17β-diol

[0111] 8β-ethyl-11β-hexyl-1,3,5(10)-triene-3,17β-diol

[0112] 11β-hexyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0113] 8β-methyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol-3-sulfamate

[0114] 8β-ethyl-11β-pentyl-1,3,5 (10)-triene-3,17β-diol-3-sulfamate

[0115] 11β-pentyl-8β-vinyl-estra-1,3,5 (10)-triene-3,17β-diol-3-sulfamate

[0116] 11β-hexyl-8β-methyl-1,3,5(10)-triene-3,17β-diol-3-sulfamate

[0117] 8β-ethyl-11β-hexyl-1,3,5(10)-triene-3,17β-diol-3-sulfamate

[0118] 11β-hexyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol-3-sulfamate

[0119] 8β-methyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol-3-acetate

[0120] 8β-ethyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol-3-acetate

[0121] 11β-pentyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol-3-acetate

[0122] 11β-hexyl-8β-methyl-1,3,5(10)-triene-3,17β-diol-3-acetate

[0123] 8β-ethyl-11β-hexyl-1,3,5(10)-triene-3,17β-diol-3-acetate

[0124] 11β-hexyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol-3-acetate.

[0125] The new compounds are suitable for inhibiting folliculogenesis and ovulation, for male contraception and for treating benign and malignant proliferative diseases of the ovary.

[0126] Unlike in the estrogen ethinylestradiol that is commonly used for hormonal contraception or else in the compounds that are to be used for contraception according to WO 00/31112, the compounds of general formula I according to the invention can be used by themselves, i.e., without the additional administration of gestagens for contraception.

[0127] As prodrugs, the esters of the 8β-substituted estratrienes according to the invention may have advantages compared to the unesterified active ingredients with respect to their method of administration, their type of action, strength and duration of action.

[0128] The sulfamates of 8β-substituted estratrienes according to the invention also have pharmacokinetic and pharmacodynamic advantages. Related effects were already described in other steroid-sulfamates (J. Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)).

[0129] In this patent application, steroids on which the 8β-substituted estra-1,3,5(10)-triene skeleton is based and which are substituted in 11-position with a β-position n-pentyl group or n-hexyl group are described for contraception, which have in vitro dissociation with respect to binding to estrogen receptor preparations from rat prostates and rat uteri and which have in vivo preferably an inhibition of folliculogenesis and ovulation: these substances have a contraceptive action over a wide dose range without influencing other estrogen-sensitive organs, such as, e.g., the uterus or the liver.

[0130] Moreover, these compounds can be used for male contraception and for treatment of benign or malignant proliferative diseases of the ovary.

[0131] The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids thereof) for the production of pharmaceutical agents, especially for the indications below.

[0132] The compounds can be used for the following indications both after oral and parenteral administration.

[0133] The novel selective estrogens that are described in this patent can be used as individual components in pharmaceutical preparations or in combination especially with GnRH-antagonists, progesterone receptor antagonists, mesoprogestins or gestagens or tissue-selective gestagens (action on A/B-form type).

[0134] The substances and the pharmaceutical agents that contain them are especially suitable for ovarian contraception, for the treatment of benign or malignant proliferative diseases of the ovary, such as, e.g., ovarian cancer, and granulosa cell tumors.

[0135] In addition, the compounds can be used for treating male fertility disorders and prostatic diseases.

[0136] The amount of a compound of general formula I′ that is to be administered varies within a wide range and can cover any effective amount. On the basis of the condition that is to be treated and the type of administration, the amount of the compound that is administered can be 0.01 μg/kg-100 mg/kg of body weight, preferably 0.04 μg/kg-1 mg/kg of body weight, per day.

[0137] In humans, this corresponds to a dose of 0.8 μg to 8 g, preferably 3.2 μg to 80 mg, daily.

[0138] According to the invention, a dosage unit contains 1.6 μg to 2000 mg of one or more compounds of general formula I′.

[0139] The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredients one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.

[0140] As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopädie der technischen Chemie [Ullman's Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., issued by Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, p. 72 and ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor K G, Aulendorf in Württemberg 1971.

[0141] The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue.

[0142] For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.

[0143] For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, very often oils with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifying agent are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

[0144] The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated so that a delayed release of active ingredient is made possible.

[0145] As inert materials, implants can contain, for example, biodegradable polymers, or synthetic silicones such as, for example, silicone rubber. In addition, for percutaneous administration, the active ingredients can be added to, for example, a patch.

[0146] For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena®) that are loaded with active compounds of general formula I for local administration, various polymers are suitable, such as, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.

[0147] To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with α-, β-, or γ-cyclodextrin or derivatives of the latter (PCT/EP95/02656).

[0148] According to the invention, the compounds of general formula I can also be encapsulated with liposomes.

[0149] Methods

[0150] Estrogen Receptor Binding Studies

[0151] The binding affinity of the new selective estrogens was tested in competitive experiments with use of 3H-estradiol as a ligand to estrogen receptor preparations from rat prostates and rat uteri. The preparation of prostate cytosol and the estrogen receptor test with prostate cytosol was carried out as described by Testas et al. (1981) (Testas, J. et al., 1981, Endocrinology 109: 1287-1289).

[0152] The preparation of rat uterus cytosol as well as the receptor test with the ER-containing cytosol were basically performed as described by Stack and Gorski, 1985 (Stack, Gorski 1985, Endocrinology 117, 2024-2032) with some modifications as described in Fuhrmann et al. (1995) (Fuhrmann, U. et al. 1995, Contraception 51: 45-52).

[0153] The substances that are described in this patent have higher binding affinity to the estrogen receptor from rat prostates than to estrogen receptors from rat uteri. In this case, it is assumed that ERβ predominates in the rat prostates over ERα, and ERα predominates in rat uteri over ERβ. Table 1 shows that the ratio of the binding to prostate and uterus receptors qualitatively coincides with the quotient of relative binding affinity (RBA) to human ERβ and ERα of rats (according to Kuiper et al. (1996), Endocrinology 138: 863-870) (Table 1). TABLE 1 Rat prost. hERα hERβ ERβ/ uterus Rat prost. ER/ Estrogen Structure RBA* RBA* ERα ER(RBA) ER(RBA) uterus ER Estradiol

100 100 1 100 100 1 Estrone

60 37 0.6 3 2 0.8 17α- Estradiol

58 11 0.2 2.4 1.3 0.5 Estriol

14 21 1.5 4 20 5 5-Andro- stenediol

6 17 3 0.1 5 50 Genisteine

5 36 7 0.1 10 100 Coumestrol

94 185 2 1.3 24 18

Sample Studies of Contraceptive Action

[0154] (a) Study of Early Folliculogenesis:

[0155] Immature female rats are hypophysectomized. This day is defined as day 0. From day 1-day 4, subcutaneous and/or oral treatment is carried out with the active substance in combination with 17β-estradiol. The animals were autopsied on day 5. The ovary is removed and analyzed macroscopically, e.g., organ weights, and microscopically, e.g., histological evaluation of the follicles, so-called follicle staging.

[0156] (b) Study of Late Folliculogenesis/Ovulation

[0157] Immature female rats are hypophysectomized. This day is defined as day 0. From day 1-day 4, subcutaneous and/or oral treatment is carried out with the active substance in combination with 17β-estradiol. On day 5, a subcutaneous injection with PMSG (pregnant mare serum gonadotrophin) is carried out. On day 7, hCG is administered intraperitoneally to trigger ovulation. On day 8, the ovary is removed and analyzed macroscopically (e.g., organ weights) and/or microscopically (e.g., histological evaluation of the follicles, so-called follicle staging). The tubes are flushed and checked for the presence of egg cells.

[0158] (c) Study of Ovulation

[0159] Immature female rats are treated (day 1) subcutaneously with PMSG (pregnant mare serum gonadotrophin) at the age of 23 days. On the same day, as well as 24 and 48 hours later, the animals receive the active substance, administered subcutaneously or orally. 54 hours after the PMSG injection, the animals receive an intraperitoneal injection of hCG to trigger ovulation. Autopsy is carried out 16 hours after the hCG is administered. The tubes are flushed and checked for the presence of eggs cells.

[0160] Another possibility to detect in vivo the dissociated estrogen action of the substances according to the invention consists in the fact that after a one-time administration of the substances in rats, effects on the expression of 5HT2a-receptor and serotonin transporter protein and mRNA levels in ERβ-rich brain areas can be measured. Compared to the effect on the serotonin receptor and transporter expression, the effect on the LH-secretion is measured. Substances with higher binding to the rat prostate—compared to the rat uterus estrogen receptor—are more potent with respect to increasing the expression of serotonin receptors and transporters, in comparison to their positive effect on the LH release. The density of serotonin receptors and transporters is determined in brain sections using radioactive ligands, and the corresponding mRNA is determined using in situ hybridization. The method is described in the literature: G. Fink & B. E. H. Sumner 1996 Nature 383: 306; B. E. H. Sumner et al. 1999 Molecular Brain Research, in press.

[0161] Production of the Compounds According to the Invention

[0162] The compounds of general formula I according to the invention are produced as described in the examples. Additional compounds of general formula I can be obtained by an analogous procedure using reagents that are homologous to the reagents that are described in the examples.

[0163] Etherification and/or esterification of free hydroxy groups is carried out according to methods that are common to one skilled in the art.

[0164] The compounds according to the invention can be present in carbon atoms 6, 7, 15, 16 and 17 as α,β-stereoisomers. In the production of compounds according to the described processes, the compounds in most cases accumulate as mixtures of the corresponding α,β-isomers. The mixtures can be separated by, for example, chromatographic processes.

[0165] According to general formula I, possible substituents can already be present in final form or in the form of a precursor even in the starting product, a substituted estrone already corresponding to the desired end product.

[0166] The introduction of a substituent or reactive precursor on carbon atom 7 by nucleophilic addition of the substituent or precursor on a 6-vinylsulfone thus is possible (DE 42 18 743 A1). In this case, 7α- and 7β-substituted compounds, which can be separated by, for example, chromatographic processes, are obtained in different proportions, based on the reactants and the selected reaction conditions.

[0167] 17-Substituents are also introduced according to known processes by nucleophilic addition of the desired substituent or a reactive precursor thereof and are optionally further built up.

[0168] The 8β-substituted estratriene-carboxylic acid esters according to the invention are produced from the corresponding hydroxy steroids analogously to processes that are also known (see, e.g., Pharmazeutische Wirkstoffe, Synthesen, Patente, Anwendungen [Pharmaceutical Active Ingredients, Syntheses, Patents, Applications]; A. Kleemann, J. Engel', Georg Thieme Verlag Stuttgart 1978. Arzneimittel, Fortschritte [Pharmaceutical Agents, Improvements] 1972 to 1985; A. Kleemann, E. Lindner, J. Engel (Editors), VCH 1987, pp. 773-814).

[0169] The estratriene-sulfamates according to the invention are available in a way that is known in the art from the corresponding hydroxy steroids by esterification with sulfamoyl chlorides in the presence of a base (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)).

[0170] Subsequent acylation of the sulfamide group results in the (N-acyl)sulfamates according to the invention, for which pharmacokinetic advantages were already detected in the case of the absence of an 8-substituent (cf. DE 195 40 233 A1).

[0171] The regioselective esterification of polyhydroxylated steroids with N-substituted and N-unsubstituted sulfamoyl chlorides is carried out according to partial protection of those hydroxyl groups that are to remain unesterified. Silyl ethers have turned out to be protective groups with selective reactivity that is suitable for this purpose, since these silyl ethers are stable under the conditions of sulfamate formation, and the sulfamate group remains intact when the silyl ethers are again cleaved off for regeneration of the residual hydroxyl group(s) still contained in the molecule (Steroids 61, 710-717 (1996)). The production of the sulfamates according to the invention with one or more additional hydroxyl groups in the molecule is also possible in that the starting material is suitable hydroxy-steroid ketones. First, depending on the goal, one or more hydroxyl groups that are present are subjected to sulfamoylation. Then, the sulfamate groups optionally can be converted with a desired acyl chloride in the presence of a base into the (N-acyl)sulfamates in question. The now present oxosulfamates or oxo-(N-acyl)sulfamates are converted by reduction into the corresponding hydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717 (1996)). Sodium borohydride and the borane-dimethyl sulfide complex are suitable as proper reducing agents.

[0172] Functionalizations at carbon atom 2 are possible by, for example, electrophilic substitution after prior deprotonation of the 2-position of the corresponding 3-(2-tetrahydropyranyl)- or 3-methyl ether with a lithium base (e.g., methyllithium, butyllithium). Thus, for example, a fluorine atom can be introduced by reaction of the C—H-activated substrate with a fluorinating reagent such as N-fluoromethane sulfonimide (WO 94/24098).

[0173] The introduction of variable substituents in rings B, C and D of the estratriene skeleton can basically be carried out according to the chemical teaching that is known to one skilled in the art, with which the corresponding estratriene derivatives that are not substituted in 8-position are produced (see, i.a.: Steroide [Steroids], L. F. Fieser, M. Fieser, Verlag Chemie, Weinheim/Bergstr., 1961; Organic Reactions in Steroid Chemistry, J. Fried, J. A. Edwards, Van Nostrand Reinhold Company, New York, Cincinnati, Toronto, London, Melbourne, 1972; Medicinal Chemistry of Steroids, F. J. Zeelen, Elsevier, Amsterdam, Oxford, New York, Tokyo, 1990). This relates to, for example, the introduction of substituents, such as hydroxyl or alkyloxy groups, alkyl, alkenyl or alkinyl groups or halogen, especially fluorine.

[0174] Substituents according to general formula I can also be introduced in the stage of estratrienes that are already substituted in 8-position, however. This can be useful or necessary especially in the case of multiple substitutions of the desired final compound.

[0175] The examples below are used for a more detailed explanation of the invention.

[0176] As starting material for such syntheses, 11-keto-estratetraene derivatives (U.S. Pat. No. 3,491,089, Tetrahedron Letters, 1967, 37, 3603), which are substituted stereoselectively in 8β-position in the reaction with diethylaluminum cyanide, are used. By subsequent reduction of the carbonyl function at C(11) and elimination of the hydroxyl group that is produced, 8β-substituted estra-1,3,5(10),9(11)-tetraenes, which in turn can be converted into 8β-aldehydes, are obtained. A functionalization, e.g., by Wittig reactions with subsequent removal of protective groups, results in the-8β-steroids according to the invention.

[0177] The 11-oxidized estradiol derivatives that are first obtained in this sequence can be further reacted to form many substitution patterns on the steroid like the double bond C(9)—C(11) according to methods that are known to one skilled in the art. For example, an 11α-hydroxy group can be converted into an 11β-fluorine atom according to the process that is described by Vorbrüggen et al.

[0178] For the production of the derivatives of 8β-substituted estra-1,3,5(10)-triene-3,16ξ-diols according to the invention without 17-substituents, mainly the following synthesis strategy is used. In this connection, the 8β-carbonyl function is protected as an acetal. After subsequent oxidation, the 17-keto steroid can be converted into a sulfonylhydrazone, in the simplest case by reaction with phenylsulfonyl hydrazide. By a degradation reaction, the formation of the C(16)-C(17) olefin is carried out (Z. Chem. 1970, 10, 221-2; Liebigs Ann. Chem. 1981, 1973-81), in which hypobromide is stored in a regio/stereocontrolled way. Reductive dehalogenation and removal of the acetal protective group at 8β opens the way for transformations to the compounds according to the invention. The 16β-alcohols that can be obtained according to this method can be converted into the 16α-epimer by known methods (Synthesis 1980, 1).

[0179] Another variant for the introduction of the hydroxyl group at C-atom 16 consists in the hydroboration of the 16(17)-double bond with sterically exacting boranes. Of this reaction, it is known that it results in 16-oxidized products (Indian J. Chem. 1971, 9, 287-8). The reaction of estra-1,3,5(10),16-tetraenes with 9-borabicyclo[3.3.1]nonane after the oxidation with alkaline hydrogen peroxide consequently produces 16α-hydroxyestratrienes. The epimeric 16β-hydroxy steroids are formed to a lesser extent in this reaction. Further transformations on 8β substituents then result in the compounds of general formula I according to the invention.

[0180] Characteristic, but not limiting synthesis processes, which are useful for providing representative substitution patterns on the estrone skeleton, also in combination with several substituents, are found in, for example: C(1) J. Chem. Soc. (C) 1968, 2915; C(7) Steroids 54, 1989, 71; C(8α) Tetrahedron Letters 1991, 743; C(8β) Tetrahedron Letters 1964, 1763; J. Org. Chem. 1970, 35, 468; C(11) J. Steroid Biochem. 31, 1988, 549; Tetrahedron 33, 1977, 609 and J. Org. Chem. 60, 1995, 5316; C(9) DE-OS 2035879; J. Chem. Soc. Perk. 1 1973, 2095; C(15) J. Chem. Soc. Perk. 1 1996, 1269.); C(13α) Mendeleev Commun. 1994, 187; C(14β) Z. Chem. 23, 1983, 410.

[0181] In the examples and in the diagrams, the following abbreviations apply:

[0182] THF=tetrahydrofuran; THP=tetrahydropyran-2-yl; DHP=dihydropyran; DMSO=dimethyl sulfoxide; MTBE=methyl-tert-butyl ether; DIBAH=diisobutylaluminum hydride; LTBAH=lithium-tri-tert.-butoxyaluminum hydride.

EXAMPLE 1

[0183] 8β-Formyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-9β-estra-1,3,5(10)-trien-11-ol (2)

[0184] 9.2 ml of DIBAH in 32 ml of absolute toluene was added in drops at 0° C. to 4.36 g of 8β-cyano steroid 1 in 105 ml of absolute toluene, and it was stirred for 2 hours at this temperature. The reaction solution was mixed in succession with 215 ml of toluene, 32 ml of saturated sodium bicarbonate solution and 4 ml of iso-propanol, and stirring was continued overnight. Then, the deposited precipitate was suctioned off, the filtrate was washed with water and saturated sodium chloride solution, dried with magnesium sulfate and concentrated by evaporation in a vacuum. The oily residue was purified on silica gel (cyclohexane/ethyl acetate 2:1), and 3.76 g of 2 was obtained as a colorless foam.

[0185] 3-Methoxy-8β-methyl-17β-(tetrahydropyran-2-yloxy)-9β-estra-1,3,5(10)-trien-11-ol (3)

[0186] 2.45 ml of hydrazinium hydroxide (80%, with water) and 1.02 g of 8β-formyl steroid 2 in 100 ml of triethylene glycol were added at room temperature to a solution of 3.44 g of potassium hydroxide in 60 ml of triethylene glycol and heated for 3 hours to 200° C. After cooling, the reaction solution was mixed with 160 ml of water and neutralized with 10% sulfuric acid. The mixture was extracted several times with diethyl ether, the organic phases were washed with water and saturated sodium chloride solution, dried with magnesium sulfate and evaporated to the dry state in a rotary evaporator. The thus obtained 965 mg of foamlike 8β-methyl steroid 3 was used without further purification in the next stage.

[0187] 3-Methoxy-8β-methyl-17β-(tetrahydropyran-2-yloxy)-9β-estra-1,3,5(10)-trien-11-one (4)

[0188] 1.06 g of PCC was added to a solution of 965 mg of alcohol 3 in 24 ml of dichloromethane and stirred for 2 more hours at room temperature. The reaction solution was filtered off from precipitate by means of a short frit on silica gel and concentrated by evaporation in a vacuum. The-residue was purified on silica gel (cyclohexane/ethyl acetate 4:1), and 671 mg of 4 was obtained as a colorless foam.

[0189] General Operating Instructions for Introducing the 11-Alkyl Chain into 3-Methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-11-ones

[0190] 10 equivalents of the corresponding alkyllithium compound was added in drops under argon at −78° C. to a suspension of 15 equivalents of anhydrous cerium(III) chloride in 5 ml/mmol of absolute THF. After 30 minutes at −78° C., a solution of 1 mmol of 11-keto steroid in 5 ml of absolute THF was added in drops to freshly produced cerium reagent. The reaction was stirred until the conversion was completed at −70 to −40° C. Then, the reaction solution was mixed with saturated ammonium chloride solution/water/diethyl ether (1:1:1), and the phases were separated. The aqueous phase was extracted several times with ether, the combined organic phases were washed with water and saturated sodium chloride solution, dried with magnesium sulfate and concentrated by evaporation in a vacuum. The oily residue was separated on silica gel by column chromatography.

[0191] 3-Methoxy-8β-methyl-11β-pentyl-17β-(tetrahydropyran-2-yloxy)-9β-estra-1,3,5(10)-trien-11α-ol (5)

[0192] 200 mg of 11-keto steroid 4 was reacted with CeCl₃/nPentLi (1 M in diethyl ether) according to general operating instructions 1.4. Column chromatography (cyclohexane/ethyl acetate 5:1) yielded 224 mg of colorless foam 5.

[0193] 3-Methoxy-8β-methyl-11-pentyl-1,3,5(10),9(11)-tetraen-17β-ol (7)

[0194] 132 mg of p-toluenesulfonic acid was added at room temperature to a solution of 120 mg of 5 in 2.5 ml of toluene. The reaction solution was heated for 90 minutes to 80° C., and after cooling to room temperature, it was mixed with water. The aqueous phase was extracted several times with toluene, the combined organic phases were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatographic purification on silica gel (cyclohexane/ethyl acetate 5:1) yielded 64 mg of a mixture (ratio 1.6:1) of α9,11-steroid 7 and the corresponding steroid with an exocyclic double bond. Separation of this mixture was carried out by means of preparative HPLC (acetonitrile/water 9:1) and yielded the α9,11-steroid 7 as a colorless solid (flash point: 148-149° C.).

[0195] 3-Methoxy-8β-methyl-11β-pentyl-1,3,5(10)-trien-17β-ol (9)

[0196] A solution of 35 mg of 7 in 1.9 ml of tetrahydrofuran/methanol (1:1) was mixed with 47 mg of palladium (10%, on carbon) and stirred under hydrogen atmosphere for about 2 weeks at room temperature. The reaction solution was filtered off from catalyst on Celite and concentrated by evaporation in a vacuum. Colorless foam 9 that was obtained (about 25 mg) was used without further purification in the next stage.

[0197] 8β-Methyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol (11)

[0198] 0.15 ml of DIBAH was added in drops at 0° C. to a solution of 25 mg of 3-methyl ether 9 in 1.35 ml of absolute toluene. Then, the reaction solution was refluxed for 4 hours. After renewed cooling to 0° C., 0.68 ml each of ethanol, ethanol/water (1:1) and semiconcentrated hydrochloric acid were added to it in succession. After the phase separation had taken place, the aqueous phase was extracted several times with toluene, the combined organic phases were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by-evaporation in a vacuum. The purification by column chromatography was carried out on silica gel (cyclohexane/ethyl acetate 3:1) and yielded 15 mg of colorless solid 11 (flash point: 150-152° C.).

EXAMPLE 2

[0199] The synthesis of substance 4 was described under Example 1, 1.1-1.3.

[0200] 11β-Hexyl-3-methoxy-8β-methyl-17β-(tetrahydropyran-2-yloxy)-9β-estra-1,3,5(10)-trien-11α-ol (6)

[0201] 166 mg of 11-keto steroid 4 was reacted with CeCl₃/nHexLi (2.5 M in hexane) according to general operating instructions 1.4. Column chromatography (cyclohexane/ethyl acetate 5:1) yielded 199 mg of colorless foam 6.

[0202] 11-Hexyl-3-methoxy-8β-methyl-1,3,5(10),9(11)-tetraen-17β-ol (8)

[0203] 81 mg of p-toluenesulfonic acid was added at room temperature to a solution of 76 mg of 6 in 1.6 ml of toluene. The reaction solution was heated for 90 minutes to 80° C., and after cooling to room temperature, it was mixed with water. The aqueous phase was extracted several times with toluene, the combined organic phases were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatographic purification on silica gel (cyclohexane/ethyl acetate 5:1) yielded 40 mg of a mixture (ratio 1.3:1) of Δ9,11-steroid 8 and the corresponding steroid with an exo-cyclic double bond. Separation of this mixture was carried out by means of preparative HPLC (acetonitrile/water 9:1) and yielded the Δ9,11-steroid 8 as a colorless solid (flash point: 147-149° C.).

[0204] 11β-Hexyl-3-methoxy-8β-methyl-1,3,5(10)-trien-17β-ol (10)

[0205] A solution of 15 mg of 8 in 0.78 ml of tetrahydrofuran/methanol (1:1) was mixed with 20 mg of palladium (10%, on carbon) and stirred under hydrogen atmosphere for about two weeks at room temperature. The reaction solution was filtered off from catalyst on Celite and concentrated by evaporation in a vacuum. Colorless foam 10 that was obtained (about 10 mg) was used without further purification in the next stage.

[0206] 11β-Hexyl-8β-methyl-1,3,5(10)-triene-3,17β-diol (12)

[0207] 0.06 ml of DIBAH was added in drops at 0° C. to a solution of 10 mg of 3-methyl ether 10 in 0.52 ml of absolute toluene. Then, the reaction solution was refluxed for 4 hours. After cooling to 0° C. was again carried out, 0.26 ml each of ethanol, ethanol/water (1:1) and semiconcentrated hydrochloric acid were added to it in succession. After phase separation was carried out, the aqueous phase was extracted several times with toluene, the combined organic phases were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The purification by column chromatography was carried out on silica gel (cyclohexane/ethyl acetate 3:1) and yielded 5 mg of a colorless solid 12 (flash point: 152-154° C.).

EXAMPLE 3

[0208] 8β-Cyano-3-methoxy-11β-pentyl-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-11α-ol (14)

[0209] 300 mg of 11-keto steroid 13 was reacted with CeCl₃/nPentLi (1 M in diethyl ether) according to general operating instructions 1.4. Column chromatography (cyclohexane/ethyl acetate 5:1) yielded 317 mg of colorless foam 14.

[0210] 8β-Cyano-3-methoxy-11-pentyl-estra-1,3,5(10),9(11)-tetraen-17β-ol (16)

[0211] 0.54 ml of POCl₃ was added in drops at 0° C. to 270 mg of 11-hydroxy steroid 14 in 5.4 ml of absolute pyridine. The cold bath was removed, and the reaction was heated for 12 hours to 60° C. Then, the reaction solution was added in drops to an ice-cooled saturated sodium bicarbonate solution. It was diluted with water and extracted several times with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The purification was carried out by column chromatography (cyclohexane/ethyl acetate 3:1). 160 mg of tetraenol 16 is obtained as a colorless foam.

[0212] 8β-Formyl-3-methoxy-11-pentyl-estra-1,3,5(10),9(11)-tetraen-17β-ol (18)

[0213] 150 mg of nitrile 16 was dissolved in 7.9 ml of absolute toluene and cooled to −10° C. Then, 1.19 ml of DIBAH (1 M in toluene) was added in drops, and the reaction solution was stirred at 0° C. until the conversion was completed. For working-up, the reaction solution was diluted with 8 ml of toluene, and 1.2 ml of saturated sodium bicarbonate solution and 0.15 ml of iso-propanol were added in drops at 0° C. The crystalline precipitate was filtered on Celite, and the solution was concentrated by evaporation. The crude imine that was thus obtained was dissolved in 4 ml of ethanol/water (5:1) and mixed with 376 mg of p-toluenesulfonic acid. The reaction solution was heated to 60° C. until the conversion was completed. Then, the reaction solution was concentrated by evaporation, the residue was taken up in ethyl acetate and washed several times with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. After purification by column chromatography (cyclohexane/ethyl acetate 3:1), 83 mg of aldehyde 18 was obtained as a colorless foam.

[0214] 8β-Formyl-3-methoxy-11β-pentyl-estra-1,3,5,(10)-trien-17β-ol (20)

[0215] 80 mg of tetraenol 18 in 4.2 ml of tetrahydrofuran/methanol (1:1) was mixed with 105 mg of palladium (10%, on carbon) and stirred for 2 weeks at room temperature. Then, it was filtered on Celite, and the 80 mg of trienol 20 that was thus obtained was used without further purification in the next stage.

[0216] 3-Methoxy-11β-pentyl-8β-vinyl-estra-1,3,5(10)-trien-17β-ol (22)

[0217] 89 mg of sodium hydride (80%) in 1.5 ml of absolute dimethyl sulfoxide was heated for 1 hour to 70° C. The gray-black solution that was obtained was added in drops at room temperature to a solution of 1.12 g of methyltriphenylphosphonium bromide in 6.2 ml of absolute dimethyl sulfoxide. The solution was colored yellow-green and was stirred for another hour at room temperature.

[0218] A solution of 80 mg of aldehyde 20 in 1 ml of absolute dimethyl sulfoxide was added in drops at room temperature to the solution of ylide. The reaction solution was stirred for 2 hours at 40° C., mixed with water at 0° C. and extracted several times with diethyl ether. The combined organic phases were washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. Purification by column chromatography (cyclohexane/ethyl acetate 3:1) yielded 64 mg of 22 as a colorless solid (flash point: 139-141° C.).

[0219] 11β-Pentyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol (24)

[0220] 0.36 ml of DIBAH was added in drops at 0° C. to a solution of 60 mg of 3-methyl ether 22 in 3.1 ml of absolute toluene. Then, it was refluxed for 4 hours. After the reaction solution was cooled to 0° C., the latter was mixed in succession with 1.6 ml of ethanol, 1.6 ml of ethanol/water (1:1) and 1.6 ml of semiconcentrated hydrochloric acid, then extracted several times with ethyl acetate, the combined organic phases were washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. Column chromatography (cyclohexane/ethyl acetate 2:1) of the residue yielded 46 mg of 24 as a colorless solid (flash point: 144-146° C.).

EXAMPLE 4

[0221] 8β-Cyano-11β-hexyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-11α-ol (15)

[0222] 300 mg of 11-keto steroid 13 was reacted with CeCl₃/nHexLi (2.5 M in hexane) according to general operating instructions 1.4. Column chromatography (cyclohexane/ethyl acetate 5:1) yielded 352 mg of colorless foam 15.

[0223] 8β-Cyano-11-hexyl-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol (17)

[0224] 0.6 ml of POCl₃ was added in drops at 0° C. to 300 mg of 11-hydroxy steroid 15. The cold bath was removed, and the reaction was heated for 12 hours to 60° C. Then, the reaction solution was added in drops to an ice-cooled saturated sodium chloride solution. It was diluted with water and extracted several times with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The purification was carried out by column chromatography (cyclohexane/ethyl acetate 3:1). 190 mg of tetraenol 17 is obtained as a colorless foam.

[0225] 8β-Formyl-11-hexyl-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol (19)

[0226] 170 mg of nitrile 17 was dissolved in 8.6 ml of absolute toluene and cooled to −10° C. Then, 1.29 ml of DIBAH (1 M in toluene) was added in drops, and the reaction solution was stirred at 0° C. until the conversion was completed. For working-up, the reaction solution was diluted with 8.6 ml of toluene, and 1.3 ml of saturated sodium bicarbonate solution and 0.16 ml of iso-propanol were added in drops at 0° C. The crystalline precipitate was filtered off on Celite, and the solution was concentrated by evaporation. The crude imine that was thus obtained was dissolved in 4.3 ml of ethanol/water (5:1) and mixed with 411 mg of p-toluenesulfonic acid. The reaction solution was heated to 60° C. until the conversion was completed. Then, the reaction solution was concentrated by evaporation, the residue was taken up in ethyl acetate and washed several times with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. After purification by column chromatography (cyclohexane/ethyl acetate 3:1), 86 mg of aldehyde 19 was obtained as a colorless foam.

[0227] 8β-Formyl-11β-hexyl-3-methoxy-estra-1,3,5(10)-trien-17β-ol (21)

[0228] 85 mg of tetraenol 19 in 4.2 ml of tetrahydrofuran/methanol (1:1) was mixed with 105 mg of palladium (10%, on carbon) and stirred for 2 weeks at room temperature. Then, it was filtered on Celite, and the 85 mg of trienol 21 that was thus obtained was used without further purification in the next stage.

[0229] 11β-Hexyl-3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol (23)

[0230] 88 mg of sodium hydride (80%) in 1.5 ml of absolute dimethyl sulfoxide was heated for 1 hour to 70° C. The gray-black solution that was obtained was added in drops at room temperature to a solution of 1.10 g of methyltriphenylphosphonium bromide in 6.2 ml of absolute dimethyl sulfoxide. The solution was colored yellow-green and was stirred for another hour at room temperature.

[0231] A solution of 82 mg of aldehyde 21 in 1 ml of absolute dimethyl sulfoxide was added in drops at room temperature to the solution of ylide. The reaction solution was stirred for 2 hours at 40° C., mixed with water at 0° C. and extracted several times with diethyl ether. The combined organic phases were washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. Purification by column chromatography (cyclohexane/ethyl acetate 3:1) yielded 67 mg of 23 as a colorless solid (flash point: 142-145).

[0232] 11β-Hexyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol (25)

[0233] 0.37 ml of DIBAH was added in drops at 0° C. to a solution of 65 mg of 3-methyl ether 23 in 3.3 ml of absolute toluene. Then, it was refluxed for 4 hours. After the reaction solution was cooled to 0° C., the latter was mixed in succession with 1.6 ml of ethanol, 1.6 ml of ethanol/water (1:1) and 1.6 ml of semiconcentrated hydrochloric acid, then extracted several times with ethyl acetate, the combined organic phases were washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. Column chromatography (cyclohexane/ethyl acetate 2:1) of the residue yielded 50 mg of 25 as a colorless solid (flash point: 148-150° C.). 

1. 8β-Substituted estra-1,3,5(10)-triene derivatives of general formula I (I)

in which R²: means hydrogen, halogen (F, Cl, Br, I); a radical R¹⁸ or R¹⁸O, whereby R¹⁸ means hydrogen, an alkyl or acyl radical (both straight-chain or branched-chain, saturated or unsaturated with up to 6 carbon atoms), a trifluoromethyl group; a radical R¹⁹SO₂O, whereby R¹⁹ means an R²⁰R²¹N group, in which R²⁰ and R²¹, independently of one another, mean hydrogen, a C₁-C₅-alkyl radical, a group C(O)R²², in which R²² means a hydrocarbon radical (optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, partially or completely halogenated) with up to 10 carbon atoms, an optionally substituted C₃-C₇-cycloalkyl radical, an optionally substituted C₄-C₁₅-cycloalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or, together with the N-atom, means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical); R³: means R¹⁸O, R¹⁹SO₂O or OC(O)R²², with R¹⁸, R¹⁹ and R²² in the meaning that is indicated under R², and in addition R¹⁸ means an aryl, hetaryl or aralkyl radical; R⁶, R^(6′): each mean hydrogen or R⁶ means an additional bond with R⁷; R⁷, R^(7′): each mean hydrogen, or R⁷ means an additional bond with R⁶; R⁸: means an alkyl or alkenyl radical (straight-chain or branched-chain, partially or completely halogenated), in each case with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical; R¹¹: means an n-pentyl or n-hexyl radical; R¹⁴ means hydrogen or an additional bond with R¹⁵; R¹⁵: means hydrogen or an additional bond with R¹⁴ or R¹⁶; R¹⁶: means hydrogen or an additional bond with R¹⁵; R^(15′), R^(16′): independently of one another, mean hydrogen, halogen, a group R¹⁸O, R¹⁹SO₂O or OC(O)R²², with R¹⁸, R¹⁹ and R²² in the meaning that is indicated under R²; R¹⁷, R^(17′): each mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², with R¹⁸, R¹⁹ and R²² in the meaning that is indicated under R²; or R¹⁷, R^(17′): together mean a group ═CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogen atom, or together represent an oxygen atom.
 2. Compounds of general formula I according to claim 1, namely 8β-Methyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol 8β-ethyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol 11β-pentyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol 11β-hexyl-8β-methyl-1,3,5(10)-triene-3,17β-diol 8β-ethyl-11β-hexyl-1,3,5(10)-triene-3,17β-diol 11β-hexyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol 8β-methyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol-3-sulfamate 8β-ethyl-11-pentyl-1,3,5(10)-triene-3,17β-diol-3-sulfamate 11β-pentyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol-3-sulfamate 11β-hexyl-8β-methyl-1,3,5(10)-triene-3,17β-diol-3-sulfamate 8β-ethyl-11β-hexyl-1,3,5(10)-triene-3,17β-diol-3-sulfamate 11β-hexyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol-3-sulfamate 8β-methyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol-3-acetate 8β-ethyl-11β-pentyl-1,3,5(10)-triene-3,17β-diol-3-acetate 11-pentyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol-3-acetate 11β-hexyl-8β-methyl-1,3,5(10)-triene-3,17β-diol-3-acetate 8β-ethyl-11β-hexyl-1,3,5(10)-triene-3,17β-diol-3-acetate 11β-hexyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol-3-acetate.
 3. Use of 8β-substituted estra-1,3,5(10)-triene derivatives of general formula I according to claim 1 for the production of pharmaceutical agents for contraception in women.
 4. Use of 8β-substituted estra-1,3,5(10)-triene derivatives of general formula I according to claim 1 for the production of pharmaceutical agents for contraception in men.
 5. Use of the estratriene derivatives of general formula I according to claim 1 for the production of pharmaceutical agents for treating benign or malignant proliferative diseases of the ovary.
 6. Use according to claim 5 for treating ovarian cancer.
 7. Use according to claim 5 for treating granulosa cell tumors.
 8. Use of the structural portion of 11β-n-pentyl- or 11β-n-hexyl-estra-1,3,5(10)-triene with a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical in each case with up to 5 carbon atoms, an ethinyl radical or prop-1-inyl radical in 8β-position as a component of the entire structure of the compounds that have a contraceptive effect on men and women without influencing other estrogen-sensitive organs such as the uterus or the liver.
 9. Use of the structural portion of the 11β-n-pentyl- or 11β-n-hexyl-estra-1,3,5(10)-triene with a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical in each case with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical in 8β-position as a component of the entire structure of compounds that are suitable for treating benign or malignant proliferative diseases of the ovary, such as ovarian cancer and granulosa cell tumors.
 10. Pharmaceutical compositions that contain at least one compound according to one of claims 1 to 3, as well as a pharmaceutically compatible vehicle.
 11. Pharmaceutical compositions according to claim 10, which in addition to at least one compound of general formula I according to claim 1 contain at least one compound that is selected from the group of GnRH antagonists, progesterone receptor antagonists, mesoprogestins, gestagens or tissue-selective gestagens. 